tbuckley/cabot-search huggingface dataset:
MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer
Authors: Ryohei Yoshida, Maria Saigi, Tetsuo Tani, Benjamin F. Springer, Hirofumi Shibata, Shunsuke Kitajima, Navin R. Mahadevan, Marco Campisi, William Kim, Yoshihisa Kobayashi, Tran C. Thai, Koji Haratani, Yurie Yamamoto, Shriram K. Sundararaman, Erik H. Knelson, Amir Vajdi, Israel Canadas, Ravindra Uppaluri, Cloud P. Paweletz, Juan J. Miret, Patrick H. Lizotte, Prafulla C. Gokhale, Pasi A. Jänne, David A. Barbie
Journal: Cancer Research (2022)

Abstract Immunotherapy has shown limited efficacy in patients with EGFR-mutated lung cancer. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third-generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity (1). However, STING activation was restrained by ectonucleosidase CD73, which is induced in MET-amplified, EGFR-TKI–resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on coinduction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR-TKI–resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR-TKI–resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI-resistant EGFR-mutated lung cancers and promote immunogenicity. Significance: MET amplification upregulates CD73 to suppress tumor cell STING induction and T-cell responsiveness in TKI-resistant, EGFR-mutated lung cancer, identifying a strategy to enhance immunogenicity and improve treatment.
Gene-environment interactions explain a substantial portion of variability of common neuropsychiatric disorders
Authors: Hanxin Zhang, Atif Khan, Andrey Rzhetsky
Journal: Cell Reports Medicine (2022)

In complex diseases, the phenotypic variability can be explained by genetic variation (G), environmental stimuli (E), and interaction of genetic and environmental factors (G-by-E effects), among which the contribution G-by-E remains largely unknown. In this study, we focus on ten major neuropsychiatric disorders using data for 138,383 United States families with 404,475 unique individuals. We show that, while gene-environment interactions account for only a small portion of the total phenotypic variance for a subset of disorders (depression, adjustment disorder, substance abuse), they explain a rather large portion of the phenotypic variation of the remaining disorders: over 20% for migraine and close to or over 30% for anxiety/phobic disorder, attention-deficit/hyperactivity disorder, recurrent headaches, sleep disorders, and post-traumatic stress disorder. In this study, we have incorporated—in the same analysis—clinical data, family pedigrees, the spatial distribution of individuals, their socioeconomic and demographic confounders, and a collection of environmental measurements.
ATF3 and CH25H regulate effector trogocytosis and anti-tumor activities of endogenous and immunotherapeutic cytotoxic T lymphocytes
Authors: Zhen Lu, Noreen McBrearty, Jinyun Chen, Vivek S. Tomar, Hongru Zhang, Gianluca De Rosa, Aiwen Tan, Aalim M. Weljie, Daniel P. Beiting, Zhen Miao, Subin S. George, Allison Berger, Gurpanna Saggu, J. Alan Diehl, Constantinos Koumenis, Serge Y. Fuchs
Journal: Cell Metabolism (2022)
Consensus Recommendations for the Use of Automated Insulin Delivery Technologies in Clinical Practice
Authors: Moshe Phillip, Revital Nimri, Richard M Bergenstal, Katharine Barnard-Kelly, Thomas Danne, Roman Hovorka, Boris P Kovatchev, Laurel H Messer, Christopher G Parkin, Louise Ambler-Osborn, Stephanie A Amiel, Lia Bally, Roy W Beck, Sarah Biester, Torben Biester, Julia E Blanchette, Emanuele Bosi, Charlotte K Boughton, Marc D Breton, Sue A Brown, Bruce A Buckingham, Albert Cai, Anders L Carlson, Jessica R Castle, Pratik Choudhary, Kelly L Close, Claudio Cobelli, Amy B Criego, Elizabeth Davis, Carine de Beaufort, Martin I de Bock, Daniel J DeSalvo, J Hans DeVries, Klemen Dovc, Francis J Doyle, Laya Ekhlaspour, Naama Fisch Shvalb, Gregory P Forlenza, Geraldine Gallen, Satish K Garg, Dana C Gershenoff, Linda A Gonder-Frederick, Ahmad Haidar, Sara Hartnell, Lutz Heinemann, Simon Heller, Irl B Hirsch, Korey K Hood, Diana Isaacs, David C Klonoff, Olga Kordonouri, Aaron Kowalski, Lori Laffel, Julia Lawton, Rayhan A Lal, Lalantha Leelarathna, David M Maahs, Helen R Murphy, Kirsten Nørgaard, David O’Neal, Sean Oser, Tamara Oser, Eric Renard, Michael C Riddell, David Rodbard, Steven J Russell, Desmond A Schatz, Viral N Shah, Jennifer L Sherr, Gregg D Simonson, R Paul Wadwa, Candice Ward, Stuart A Weinzimer, Emma G Wilmot, Tadej Battelino
Journal: Endocrine Reviews (2022)

Abstract The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage.
3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk
Authors: Chun Su, Long Gao, Catherine L. May, James A. Pippin, Keith Boehm, Michelle Lee, Chengyang Liu, Matthew C. Pahl, Maria L. Golson, Ali Naji, Struan F.A. Grant, Andrew D. Wells, Klaus H. Kaestner
Journal: Cell Metabolism (2022)
Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood
Authors: Nicholas Borcherding, Wentong Jia, Rocky Giwa, Rachael L. Field, John R. Moley, Benjamin J. Kopecky, Mandy M. Chan, Bin Q. Yang, Jessica M. Sabio, Emma C. Walker, Omar Osorio, Andrea L. Bredemeyer, Terri Pietka, Jennifer Alexander-Brett, Sharon Celeste Morley, Maxim N. Artyomov, Nada A. Abumrad, Joel Schilling, Kory Lavine, Clair Crewe, Jonathan R. Brestoff
Journal: Cell Metabolism (2022)
Excitatory SST neurons in the medial paralemniscal nucleus control repetitive self-grooming and encode reward
Authors: Jingjing Sun, Yuan Yuan, Xiaohua Wu, Anqi Liu, Jingjie Wang, Shuo Yang, Bing Liu, Yalei Kong, Lizhao Wang, Kai Zhang, Qian Li, Siyu Zhang, Tifei Yuan, Tian-Le Xu, Ju Huang
Journal: Neuron (2022)

The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive behaviors affect anxiety regulation is unclear. Here, we identify that the excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPLSST neurons) in mice promote self-grooming and encode reward. MPLSST neurons display prominent grooming-related neuronal activity. Loss of function of MPLSST neurons impairs both self-grooming and post-stress anxiety alleviation. Activation of MPLSST neurons is rewarding and sufficient to drive reinforcement by activating dopamine (DA) neurons in the ventral tegmental area (VTA) and eliciting dopamine release. The neuropeptide SST facilitates the rewarding impact of MPLSST neurons. MPLSST neuron-mediated self-grooming is triggered by the input from the central amygdala (CeA). Our study reveals a dual role of CeA-MPLSST-VTADA circuit in self-grooming and post-stress anxiety regulation and conceptualizes MPLSST neurons as an interface linking the stress and reward systems in mice.
Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3–ABCB1 Signaling in Hepatocellular Carcinoma
Authors: Beiyuan Hu, Tiantian Zou, Wei Qin, Xiaotian Shen, Yinghan Su, Jianhua Li, Yang Chen, Ze Zhang, Haoting Sun, Yan Zheng, Chao-Qun Wang, Zhengxin Wang, Tian-En Li, Shun Wang, Le Zhu, Xufeng Wang, Yan Fu, Xudong Ren, Qiongzhu Dong, Lun-Xiu Qin
Journal: Cancer Research (2022)

Abstract Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR–STAT3–ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft–dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR–STAT3–ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease. Significance: HCC cells acquire resistance to lenvatinib by activating the EGFR–STAT3–ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.
The cAMP/PKA/CREB and TGFβ/SMAD4 Pathways Regulate Stemness and Metastatic Potential in Colorectal Cancer Cells
Authors: Teruaki Fujishita, Yasushi Kojima, Rie Kajino-Sakamoto, Emi Mishiro-Sato, Yasuhiro Shimizu, Waki Hosoda, Rui Yamaguchi, Makoto Mark Taketo, Masahiro Aoki
Journal: Cancer Research (2022)

This study identifies signaling pathways essential for maintaining the stemness and metastatic potential of colorectal cancer cells and proposes CREB as a therapeutic target in metastatic colorectal cancer.
Mechanisms regulating neutrophil responses in immunity, allergy, and autoimmunity
Authors: Alaz Özcan, Onur Boyman
Journal: Allergy (2022)

Neutrophil granulocytes, or neutrophils, are the most abundant circulating leukocytes in humans and indispensable for antimicrobial immunity, as exemplified in patients with inborn and acquired defects of neutrophils. Neutrophils were long regarded as the foot soldiers of the immune system, solely destined to execute a set of effector functions against invading pathogens before undergoing apoptosis, the latter of which was ascribed to their short life span. This simplistic understanding of neutrophils has now been revised on the basis of insights gained from the use of mouse models and single-cell high-throughput techniques, revealing tissue- and context-specific roles of neutrophils in guiding immune responses. These studies also demonstrated that neutrophil responses were controlled by sophisticated feedback mechanisms, including directed chemotaxis of neutrophils to tissue-draining lymph nodes resulting in modulation of antimicrobial immunity and inflammation. Moreover, findings in mice and humans showed that neutrophil responses adapted to different deterministic cytokine signals, which controlled their migration and effector function as well as, notably, their biologic clock by affecting the kinetics of their aging. These mechanistic insights have important implications for health and disease in humans, particularly, in allergic diseases, such as atopic dermatitis and allergic asthma bronchiale, as well as in autoinflammatory and autoimmune diseases. Hence, our improved understanding of neutrophils sheds light on novel therapeutic avenues, focusing on molecularly defined biologic agents.
Resensitization in suspected penicillin allergy
Authors: Inmaculada Doña, Lucia Guidolin, Gádor Bogas, Elisa Olivieri, Marina Labella, Michele Schiappoli, Rocío Sáenz de Santa María, Annarita Dama, María Salas, Gianenrico Senna, Patrizia Bonadonna, María José Torres
Journal: Allergy (2022)

Abstract Background The diagnosis of allergic reactions to penicillins (AR‐PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and specific IgE in serum, and even to tolerance to the drug involved. However, STs may become positive after subsequent exposure to the culprit drug (resensitization), with the risk of inducing potentially severe reactions. The exact rate of resensitization to penicillins is unknown, ranging from 0% to 27.9% in published studies. Objectives To analyze the rate of resensitization in patients with suggestive AR‐PEN by repeating STs (retest) after an initial evaluation (IE). Material and Methods Patients with suspected AR‐PEN were prospectively evaluated between 2017 and 2020. They underwent STs, and a randomized group also underwent a drug provocation test (DPT) with the culprit. Only patients with negative STs and/or DPT were included. All included cases were retested by STs at 2–8 weeks. Results A total of 545 patients were included: 296 reporting immediate reactions (IRs) and 249 non‐immediate reactions (NIRs). Eighty (14.7%) cases had positive results in retest (RT+): 63 (21.3%) IRs and 17 (6.8%) NIRs ( p &lt; 0.0001). The rate of RT+ was higher in anaphylaxis compared with all other reactions (45.8% vs 9.1%, p &lt; 0.0001). The risk of RT+ was higher from the fifth week after IE (OR: 4.64, CI: 2.1–11.6; p &lt; 0.001) and increased with the patient's age (OR: 1.02; CI: 1.01–1.04; p = 0.009). Conclusions Due to the high rate of resensitization, retest should be included in the diagnostic algorithm of IRs to penicillins after an initial negative study, especially in anaphylaxis, to avoid potentially severe reactions after subsequent prescriptions of these drugs.
CD69 expression on regulatory T cells protects from immune damage after myocardial infarction
Authors: Rafael Blanco-Domínguez, Hortensia de la Fuente, Cristina Rodríguez, Laura Martín-Aguado, Raquel Sánchez-Díaz, Rosa Jiménez-Alejandre, Iker Rodríguez-Arabaolaza, Andrea Curtabbi, Marcos M. García-Guimaraes, Alberto Vera, Fernando Rivero, Javier Cuesta, Luis J. Jiménez-Borreguero, Alberto Cecconi, Albert Duran-Cambra, Manel Taurón, Judith Alonso, Héctor Bueno, María Villalba-Orero, Jose Antonio Enríquez, Simon C. Robson, Fernando Alfonso, Francisco Sánchez-Madrid, José Martínez-González, Pilar Martín
Journal: Journal of Clinical Investigation (2022)

Increasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69–/– mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Tregs into Cd69–/– mice after LAD ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.
Effect of acute TLR4 inhibition on insulin resistance in humans
Authors: Hanyu Liang, Nattapol Sathavarodom, Claudia Colmenares, Jonathan Gelfond, Sara E. Espinoza, Vinutha Ganapathy, Nicolas Musi
Journal: Journal of Clinical Investigation (2022)

BackgroundStudies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.MethodsIn protocol I, 10 lean, healthy individuals received the following 72-hour i.v. infusions in a randomized crossover design: saline (30 mL/h) plus vehicle; Intralipid (30 mL/h) plus vehicle; or Intralipid (30 mL/h) plus eritoran (12 mg i.v. every 12 hours). In protocol II, also a randomized crossover design, 9 nondiabetic individuals with obesity received eritoran or vehicle for 72 hours. The effect of eritoran was assessed with euglycemic hyperinsulinemic clamps.ResultsIn protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG) concentrations, fasting plasma insulin (FPI) concentrations, and the homeostatic model assessment of insulin resistance (HOMA-IR) index by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations of these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in individuals with obesity and insulin resistance (protocol II).ConclusionsAcute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 in metabolic dysfunction in humans.Trial registrationClinicalTrials.gov NCT02321111 and NCT02267317.FundingNIH grants R01DK080157, P30AG044271, P30AG013319, and UL1TR002645.
BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis
Authors: Guizhen Zhao, Yang Zhao, Haocheng Lu, Ziyi Chang, Hongyu Liu, Huilun Wang, Wenying Liang, Yuhao Liu, Tianqing Zhu, Oren Rom, Yanhong Guo, Lin Chang, Bo Yang, Minerva T. Garcia-Barrio, Jiandie D. Lin, Y. Eugene Chen, Jifeng Zhang
Journal: Journal of Clinical Investigation (2022)

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both angiotensin II– (Ang II–) and elastase-induced AAA formation in mice, with a significant increase in elastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMCs resulted in loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex and suppressing VSMC inflammation by promoting a repressive chromatin state of NF-κB target genes as well as preventing VSMC apoptosis through transcriptional activation of KLF5-dependent B cell lymphoma 2 (BCL2) expression. Our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA.
Updates in biologic therapy for chronic rhinosinusitis with nasal polyps and <scp>NSAID</scp>‐exacerbated respiratory disease
Authors: Xinni Xu, Sietze Reitsma, De Yun Wang, Wytske J. Fokkens
Journal: Allergy (2022)

Abstract Chronic rhinosinusitis with nasal polyps (CRSwNP) associated with type 2 inflammation and non‐steroidal anti‐inflammatory drug (NSAID)‐exacerbated respiratory disease (N‐ERD) can be difficult to control with standard medical therapy and sinus surgery. In this group, biologicals are potentially promising treatment options. The phase III clinical trials for omalizumab, dupilumab, mepolizumab and benralizumab in CRSwNP have demonstrated favourable outcomes. Moving forward, direct comparisons among biologicals, refining patient selection criteria for specific biologicals, determining optimal treatment duration and monitoring long‐term outcomes are areas of emerging interest. This review summarizes the clinical evidence from the recent 2 years on the role of biologicals in severe CRSwNP and N‐ERD, and proposes an approach towards decision‐making in their use.